Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

Details

• Personal Author:
  Apopa PL ; Hu X ; Kan YW ; Ma Q ; Roberts, Jennifer R.
• Description:
  Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2-/- female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is shown to selectively destroy small ovarian follicles, resulting in early depletion of functional follicles. Treatment with VCD induces apoptotic death in cultured cells and in ovarian follicles, suggesting apoptosis as a mechanism of follicle loss. Loss of Nrf2 function blocks the basal and inducible expression of microsomal epoxide hydrolase, a key enzyme in the detoxification of VCD, and increases the oxidative stress in cells that is further exacerbated by VCD. Foxo3a, a repressor in the early stages of follicle activation, displays reduced expression in Nrf2-/- ovaries, causing accelerated growth of follicles in the absence of exposure to exogenous chemicals. Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization. This study demonstrates that Nrf2 serves as an essential sensor and regulator of chemical homeostasis in ovarian cells, protecting the cells from toxic chemicals by controlling metabolic detoxification, reactive oxygen species defense, and Foxo3a expression. In addition, these findings raise the possibility that exposure to environmental or occupational ovotoxicants plays a role in the premature ovarian failure commonly associated with infertility and premature aging in women. [Description provided by NIOSH]
• Subjects:
  Animals Antioxidants Biochemistry Cells, Cultured Energy Metabolism Environmental Monitoring Genetics Hazardous Substances Laboratories Occupational Health Safety

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• Keywords:
  Animal-studies Antioxidation Biochemical-analysis Cell-cultures Exposure-assessment Genetic-factors Laboratory-animals Metabolism Toxic-effects Toxins
• ISSN:
  0270-7306
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  26
• Issue:
  3
• NIOSHTIC Number:
  nn:20029401
• Citation:
  Mol Cell Biol 2006 Feb; 26(3):940-954
• Contact Point Address:
  Receptor Biology Laboratory, TMBB/HELD/NIOSH/CDC, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505, USA
• Email:
  qam1@cdc.gov
• Federal Fiscal Year:
  2006
• Peer Reviewed:
  True
• Source Full Name:
  Molecular and Cellular Biology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:83bcef0dc9f2a23a13ca0c4c52d0a0d85f54f6bcadabb94ec2a757cd2a0a3124042c6e3a31275e169281a25dcc7171d35522d689e6837777a50cda74dd5ed1af
• Download URL:
  https://stacks.cdc.gov/view/cdc/190387/cdc_190387_DS1.pdf
• File Type:
  [PDF - 1.95 MB ]